scholarly journals Computational Modeling Explains the Multi Sterol Ligand Specificity of the N-Terminal Domain of Niemann–Pick C1-Like 1 Protein

ACS Omega ◽  
2019 ◽  
Vol 4 (25) ◽  
pp. 20894-20904
Author(s):  
Vasanthanathan Poongavanam ◽  
Jacob Kongsted ◽  
Daniel Wüstner
Keyword(s):  
Computational Modeling ◽  
Ligand Specificity ◽  
Terminal Domain ◽  
Niemann Pick

scholarly journals NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes

2008 ◽  
Vol 105 (40) ◽  
pp. 15287-15292 ◽  
Author(s):  
Rodney E. Infante ◽  
Michael L. Wang ◽  
Arun Radhakrishnan ◽  
Hyock Joo Kwon ◽  
Michael S. Brown ◽  
...  
Keyword(s):  
Amino Acids ◽  
Lipid Bilayers ◽  
Clinical Phenotype ◽  
Phosphatidylcholine Liposomes ◽  
Terminal Domain ◽  
Naturally Occurring ◽  
Membrane Bound ◽  
Niemann Pick ◽  
Lysosomal Proteins

Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann–Pick C1 (NPC1) and soluble Niemann–Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25–264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [3H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype.

scholarly journals Structural study on ligand specificity of human vitamin B12 transporters

2007 ◽  
Vol 403 (3) ◽  
pp. 431-440 ◽  
Author(s):  
Jochen Wuerges ◽  
Silvano Geremia ◽  
Lucio Randaccio
Keyword(s):  
Vitamin B12 ◽  
Electrostatic Interactions ◽  
Intrinsic Factor ◽  
Point Of View ◽  
Tryptophan Residue ◽  
Ligand Specificity ◽  
Binding Assays ◽  
Terminal Domain ◽  
Affinity Constants ◽  
Structural Point

Studies comparing the binding of genuine cobalamin (vitamin B12) to that of its natural or synthetic analogues have long established increasing ligand specificity in the order haptocorrin, transcobalamin and intrinsic factor, the high-affinity binding proteins involved in cobalamin transport in mammals. In the present study, ligand specificity was investigated from a structural point of view, for which comparative models of intrinsic factor and haptocorrin are produced based on the crystal structure of the homologous transcobalamin and validated by results of published binding assays. Many interactions between cobalamin and its binding site in the interface of the two domains are conserved among the transporters. A structural comparison suggests that the determinant of specificity regarding cobalamin ligands with modified nucleotide moiety resides in the β-hairpin motif β3-turn-β4 of the smaller C-terminal domain. In haptocorrin, it provides hydrophobic contacts to the benzimidazole moiety through the apolar regions of Arg357, Trp359 and Tyr362. Together, these large side chains may compensate for the missing nucleotide upon cobinamide binding. Intrinsic factor possesses only the tryptophan residue and transcobalamin only the tyrosine residue, consistent with their low affinity for cobinamide. Relative affinity constants for other analogues are rationalized similarly by analysis of steric and electrostatic interactions with the three transporters. The structures also indicate that the C-terminal domain is the first site of cobalamin-binding since part of the β-hairpin motif is trapped between the nucleotide moiety and the N-terminal domain in the final holo-proteins.

N-terminal domain of the cholesterol transporter Niemann–Pick C1-like 1 (NPC1L1) is essential for α-tocopherol transport

2017 ◽  
Vol 486 (2) ◽  
pp. 476-480 ◽  
Author(s):  
Jun Kamishikiryo ◽  
Misaki Haraguchi ◽  
Shunsuke Nakashima ◽  
Yuka Tasaka ◽  
Hiroe Narahara ◽  
...  
Keyword(s):  
Terminal Domain ◽  
Niemann Pick

scholarly journals Signature of N-terminal domain (NTD) structural re-orientation in NPC1 for proper alignment of cholesterol transport: Molecular dynamics study with mutation

2020 ◽  
Author(s):  
Hye-Jin Yoon ◽  
Hyunah Jeong ◽  
Hyung Ho Lee ◽  
Soonmin Jang
Keyword(s):  
Molecular Dynamics ◽  
Full Length ◽  
Cholesterol Transport ◽  
Cholesterol Trafficking ◽  
Terminal Domain ◽  
Loop Region ◽  
Niemann Pick ◽  
Dynamics Simulations ◽  
And Function ◽  
Lumenal Domain

AbstractThe lysosomal membrane protein NPC1 (Niemann-Pick type C1) and NPC2 (Niemann-Pick type C2) are main players of cholesterol control in lysosome and it is known that mutation on these proteins leads to cholesterol trafficking related disease, called Niemann-Pick disease type C (NPC) disease. The mutation R518W or R518Q on NPC1 is one of such disease-related mutations, causing reduced cholesterol transport by half, resulting in accumulation of cholesterol and lipids in late endosomal/lysosomal region of the cell. Even though there has been significant progress in understanding cholesterol transport by NPC1 in combination with NPC2, especially after the structural determination of full length NPC1 in 2016, many details such as interaction of full length NPC1 with NPC2, molecular motions responsible for cholesterol transport during and after this interaction, and structure and function relations of many mutations are still not well understood.We report the extensive molecular dynamics simulations to gain insight into the structure and motions of NPC1 lumenal domain for cholesterol transport and disease behind the mutation (R518W). It is found that the mutation induces structural shift of NTD (N-terminal domain), toward the loop region in MLD (middle lumenal domain), which is believed to play central role in interaction with NPC2 protein, such that the interaction with NPC2 protein might be less favorable compare to wild NPC1. Also, the simulation indicates the possible re-orientation of the NTD, aligning to form an internal tunnel, after receiving the cholesterol from NPC2 with wild NPC1 unlike the mutated one, a possible pose for further action in cholesterol trafficking. We believe the current study can provide better understanding on the cholesterol transport by NPC1, especially the role of NTD of NPC1, in combination with NPC2 interaction.Synopsismodeling study of cholesterol binding protein NPC1

scholarly journals Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

2020 ◽  
Vol 16 (10) ◽  
pp. e1007554
Author(s):  
Vikas Dubey ◽  
Behruz Bozorg ◽  
Daniel Wüstner ◽  
Himanshu Khandelia
Keyword(s):  
Terminal Domain ◽  
Niemann Pick ◽  
Cholesterol Binding

scholarly journals Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain

2019 ◽  
Author(s):  
Vikas Dubey ◽  
Behruz Bozorg ◽  
Daniel Wüstner ◽  
Himanshu Khandelia
Keyword(s):  
Conformational Dynamics ◽  
Feedback Mechanism ◽  
Lysosomal Membrane ◽  
Protein Activity ◽  
Terminal Domain ◽  
Allosteric Effector ◽  
Lysosomal Accumulation ◽  
Regulate Protein ◽  
Niemann Pick ◽  
Cholesterol Binding

AbstractLysosomal accumulation of cholesterol is a hallmark of Niemann Pick type C (NPC) disease caused by mutations primarily in the lysosomal membrane protein NPC1. NPC1 contains a transmembrane sterol sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood. Using atomistic simulations, we show that the binding of cholesterol to the SSD of NPC1 suppresses conformational dynamics of the luminal domains which otherwise bring the luminal N-terminal domain (NTD) closer to the lipid bilayer. The presence of an additional 20% membrane cholesterol has negligible impact on this process. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 which controls cholesterol abundance in the lysosomal membrane.

Computational Analysis of Sterol Ligand Specificity of the Niemann Pick C2 Protein

Biochemistry ◽  
2016 ◽  
Vol 55 (36) ◽  
pp. 5165-5179 ◽  
Author(s):  
Vasanthanathan Poongavanam ◽  
Jacob Kongsted ◽  
Daniel Wüstner
Keyword(s):  
Computational Analysis ◽  
Ligand Specificity ◽  
Niemann Pick
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